The invention relates to compositions for administering pharmaceuticals orally without spilling. More specifically, the invention relates to vehicles and devices for delivering a variety of pharmaceutical products.
Syrups, elixirs, solutions, and suspensions are traditional dosage forms for oral medication. These liquid formulations are typically measured by pouring into a spoon, but this approach has the great drawback of spillage. The risk of spillage can cause people to underfill the spoon, leading to inaccurate dosage. With elderly people, children, and the infirm, difficulty in filling a spoon with a liquid and bringing it to the mouth can be a serious impediment to administering the medicine. Solid formulations such as pills, tablets, and capsules are also difficult for children and for elderly, infirm people to swallow.
Tachon et al., U.S. Pat. No. 5,300,302, teaches a pump dispenser for administering a metered dosage of a drug formulation. This requires a complex mechanical device and formulation properties suitable for pumping.
Gorman et al., U.S. Pat. No. 5,288,479, teaches a thickened pharmaceutical preparation comprising a hexitol and a seaweed polysaccharide. Such compositions tend to separate, and require a metered dispenser.
Ross, U.S. application Ser. No. 08/114,315, EP 95939059.2 (commonly owned with this application and incorporated herein by reference), teaches semi-solid formulations and a delivery system. However, there remains a need for more stable compositions with improved rheological characteristics. There is also a need for a reliable test system for identifying optimal formulations.
The invention relates to a drug delivery system including a combination of a squeezable container, a dispenser, and a semi-solid pharmaceutical formulation. Each of these elements of the drug delivery system has certain characteristics so that the combination (a) allows easy administration (b) of a measured amount of the drug, (c) from a convenient, preferably tamper-resistant and child-proof container, (d) with predetermined resistance to spilling, (e) while providing a suitable storage stable pharmaceutical composition with compatible components. These properties result from a variety of physico-chemical characteristics of the formulation optimized in conjunction with the type of container and dispenser.
An embodiment of the invention is a method for obtaining a suitable spill-resistant formulation comprising combining a systemic pharmaceutical agent suitable for oral administration with a semi-solid vehicle, and then conducting the following tests of the formulation: measuring initial viscosity, measuring yield value, extruding the formulation into a spoon from a container through a 1 to 5 mm orifice, observing the spreading/leveling characteristic of the formulation in the spoon, measuring spill resistance by spill start time after at least one of spoon vibration, spoon inversion, and spoon tilting at 90 degrees, and measuring viscosity after storing at elevated temperature for at least one month.
The compositions of the invention are light, water-soluble gels, which are easy to clean from a spoon bowl, and from any other surfaces which they may contact. The surface tensions of the formulations are sufficiently high to provide desirable spill-resistance, while allowing the product to be sufficiently free-flowing. In the examples of the prior Ross application, the viscosity was higher, providing a firm, spill-proof product. Here, the range of viscosity is lower, providing a freer-flowing, better leveling product, that is easier to administer with spill-resistance, but one which is more prone to spillage than the prior formulations. Thus, while the prior compositions may be considered spill-proof, the compositions set forth here are optimally xe2x80x9cspill-resistantxe2x80x9d but have other superior characteristics e.g. as to measurability and dispensability.
Preferred characteristics for the formulation and the method are as follows. The viscosity, when measured by a Brookfield Viscometer using xe2x80x9cCxe2x80x9d spindle at 20 rpm and 20-25 degrees Celsius, is between about 5,000 to 50,000 cps, preferably less than 25,000 cps. Surprisingly, a most preferred range for a formulation to be squeezed from a tube is between about 7,000 and about 12,500 cps. The formulation does not start to spill until after about 30 seconds when vibrated at a frequency of about 2-8 per second, and an amplitude up to about 1 inch. The spill start time on spoon inversion is at least about 20-30 seconds for a plastic 8 ml spoon, longer than for a syrup, and within about 1-20 seconds on spoon tilting at 90 degrees, which is slower than a syrup, but faster than prior non-spill formulations.
Preferred compositions have good shelf life, meaning that the preferred characteristics are retained after at least three months storage at a temperature of at least about 40 degrees Celsius at 75% humidity, which extrapolates under normal assumptions accepted by the U.S. Food and Drug Administration to two years shelf-life stability at room temperature. Surprisingly, in preferred embodiments using carboxyvinyl polymers such as Carbopol 974, stability may be accomplished by minimizing sodium containing substances from the formulation. Also, the Carbopol has a surprising taste masking effect for bitter drugs like acetaminophen.
Preferred compositions have Carbopol 974 in a concentration of from about 0.25% to below about 1%, in contrast to prior compositions having 1% or more. Other preferred compositions have a cellulose derivative in an amount of from about 2.5% to 3.3%, more preferably less than about 2%. A particularly preferred composition has about 1% microcrystalline cellulose and less than about 2.0% sodium carboxymethylcellulose, in contrast to prior formulations with about 2.4 to 2.8% CMC.
The configuration of the container, closure device, and receptacle and the consistency of the formulation are selected so that in response to pressure on the container when the channel closure device is open, a single predetermined unit dose of the pharmaceutical composition can be easily squeezed by manual pressure from the container through the channel into the receptacle, measured, and administered orally without spilling any of the composition from the container or the receptacle. The device may be as shown in the commonly owned Ross application or any other suitable device available to a person of ordinary skill.
This invention succeeds where previous efforts failed to provide a simple, stable, useful system of spill-resistant pharmaceutical formulations. This invention solves a previously unrecognized problem as to the rheological properties that must be optimized for a successful spill-resistant formulation.
This invention is in a crowded and mature art of oral medications, in which new dosage forms are constantly sought, at great expense and at high profit. Nonetheless, no similar composition or system has been previously discovered. Indeed, semi-solid formulations run contrary to the conventional wisdom of using either liquid or solid dosage forms.
This invention omits complex mechanical elements employed in the prior art such as pumps, syringes, and elaborate measuring vessels without loss of ability, and indeed with improved performance. This provides advantages in manufacturing, distribution, and waste disposal, and other economies as well.
The drug delivery system of the invention is counter-intuitive and inventive as indicated by the lack of commercially available embodiments of semi-solid formulations for oral administration of pharmaceutical agents. The resistant drug delivery system of the invention solves such longstanding problems with liquid formulations as spillage, and resultant underfilling of measuring spoons. The drug delivery system of the invention also overcomes the disadvantages of solid dosage forms, such as being hard to swallow.
The inventive formulations are semi-solid, not liquid or solid. Palatability, stability (a long shelf life) compatibility of components, and ease of administration of a required dose are provided. The system allows effortless administration of predetermined measured doses to children and adults with motor problems, without spilling. It is easier to measure than a liquid and easier to swallow than a solid.
A spill-resistant pharmaceutical formulation for oral administration from a squeezable container comprises a per-unit dose effective amount of a pharmaceutical agent in a suitable vehicle comprising a liquid base and a thickening agent, the formulation consisting of mutually compatible components and having the following properties: a viscosity within the range of about 7500 to about 25,000 cps using a Brookfield Viscometer with a xe2x80x98Cxe2x80x99 spindle with Helipath movement at a spindle speed of 20 rpm and 20-25xc2x0 C; a viscometric yield value of a semi-solid; a spill-resistant consistency permitting the composition to be squeezed by light manual pressure through a channel of about 1-5 mm, to spread in a spoon bowl sufficiently quickly for accurate measurement, and to remain in the spoon bowl without spilling for at least several seconds on spoon inversion and tilting at 90 degrees, and for at least one minute upon spoon vibration; homogeneity such that the components do not separate under conditions of use, and a storage stability such that the foregoing properties are retained for at least three months of storage at accelerated stability conditions of elevated temperature and humidity.
The viscosity is preferably between about 7000 and about 25,000 cps, more preferably between about 7500 and about 12,500 cps, after storage for three months at a temperature of at least 40 degrees C.
The formulation preferably comprises about 0.25 to about 1% water-soluble carboxyvinyl polymer and is preferably essentially free of sodium. The liquid base preferably comprises glycerin and sorbitol, and the thickening agent preferably comprises sodium carboxymethylcellulose in an amount of less than about 2.5% and microcrystalline cellulose in an amount of about 0.9%. The formulation preferably comprises glycerin and sorbitol as a solution of about 70% in water, the concentration of glycerin and sorbitol solution being about 40%, and microcrystalline cellulose in an amount of about 0.9%, and carboxymethylcellulose in an amount of about 0.9% to about 2.4%.
The pharmaceutical agent is preferably selected from the group consisting of an analgesic, non-steroidal anti-inflammatory, antihistamine, cough suppressant, expectorant, bronchodilator, anti-infective, CNS active drug, cardiovascular drug, antineoplastic, cholesterol-lowering drug, anti-emetic, vitamin, mineral supplement and fecal softener. The pharmaceutical agent may be selected from the group consisting of acetaminophen, aspirin, ibuprofen, diphenhydramine, dextromethorphan, guafenesin, pseudoephedrine, carbidopa, levodopa, terfenadine, ranitidine, ciprofloxacin, triazolam, fluconazole, propranolol, acyclovir, fluoxetine, enalapril, diltiazem, lovastatin and a pharmaceutically acceptable salt or ester thereof.
The liquid base is preferably in an amount of about 45 weight-percent to about 95 weight-percent, comprising a palatable solvent, selected from the group consisting of water, propylene glycol, polyethylene glycol, glycerin, and mixtures thereof, and the thickening agent is preferably in an amount of about 1 weight-percent to about 55 weight-percent, and is selected from the group consisting of starch, modified starch, sodium carboxymethyl cellulose in an amount of less than about 2%, microcrystalline cellulose, hydroxypropyl cellulose, other cellulose derivatives, acacia, tragacanth, pectin, gelatin, polyethylene glycol, and water-soluble carboxyvinyl polymers in a concentration of less than 1% and in the absence of a sodium component. The thickening agent is preferably a cellulose derivative in an amount of about 0.9 to 2.5 weight % by volume.
The invention further encompasses a pharmaceutical delivery system comprising the formulation of the invention in a squeezable container from which a unit dose of the formulation may be squeezed, either a single dose or multiple doses of the formulation. The system may further comprise a spoon bowl receptacle attachable to the container.
A method for producing a formulation for a spill-resistant pharmaceutical composition comprises combining a per-unit dose effective amount of a pharmaceutical agent with suitable vehicle components comprising a liquid base and a thickening agent, testing the formulation for acceptance criteria for a composition that can be easily squeezed from a container into a receptacle, measured, and administered orally without spilling the composition from the container or the receptacle, and accepting a formulation that satisfies the acceptance criteria, the acceptance criteria comprising:
viscosity within the range 2500-75,000, preferably 5000-45,000 cps equivalent using a Brookfield Viscometer with a xe2x80x98Cxe2x80x99 spindle with Helipath movement at 20 RPM and 20-25xc2x0 C.;
viscometric yield value,
ease of administration comprising (a) extrudability under light manual pressure from a squeezable container or a proxy (e.g. a syringe with a 5 mm orifice), and (b) spreadability in a spoon bowl measured by extruding the formulation into a spoon bowl and determining whether the material spreads to the edges of the spoon bowl,
spill resistance in the spoon bowl during at least one test period of vibrations, inversion, and tilting, while monitoring whether the product spills from the spoon,
mutual compatibility of the components such that they do not separate, and
shelf-life of two years at room temperatures as demonstrated by 3-months accelerated stability testing at elevated temperature and humidity.
The test spoon may be plastic and the test period for vibrations at least about five minutes, the test period for inversion at least about 30 seconds, and the test period for tilting at least about 20 seconds. The spreadability is such that the formulation spreads to the edge of the spoon within seconds. The method preferably comprises testing a vehicle without the pharmaceutical agent for at least one of the acceptance criteria, combining the pharmaceutical agent with the vehicle, and then testing the formulation for all acceptance criteria.